An international working group consensus report for the prioritization of molecular biomarkers for Ewing sarcoma

Abstract

The advent of dose intensified interval compressed therapy has improved event-free survival for patients with localized Ewing sarcoma (EwS) to 78% at 5 years. However, nearly a quarter of patients with localized tumors and 60-80% of patients with metastatic tumors suffer relapse and die of disease. In addition, those who survive are often left with debilitating late effects. Clinical features aside from stage have proven inadequate to meaningfully classify patients for risk-stratified therapy. Therefore, there is a critical need to develop approaches to risk stratify patients with EwS based on molecular features. Over the past decade, new technology has enabled the study of multiple molecular biomarkers in EwS. Preliminary evidence requiring validation supports copy number changes, and loss of function mutations in tumor suppressor genes as biomarkers of outcome in EwS. Initial studies of circulating tumor DNA demonstrated that diagnostic ctDNA burden and ctDNA clearance during induction are also associated with outcome. In addition, fusion partner should be a pre-requisite for enrollment on EwS clinical trials, and the fusion type and structure require further study to determine prognostic impact. These emerging biomarkers represent a new horizon in our understanding of disease risk and will enable future efforts to develop risk-adapted treatment.

Fig. 1. Schematic representation of potential prognostic biomarkers.

In this review we evaluate multiple molecular biomarkers with the potential to inform testing of risk-stratified therapy on a future therapeutic trial. Here we provide a graphical representation of the biomarkers evaluated.

Fig. 2. Poor prognostic molecular features of Ewing sarcoma tumors.

Survival curves demonstrating the prognostic impact of 1q gain shown here are adapted with permission from Mackintosh C. et al., Oncogene, 2012 (a) and Tirode F. et al., Cancer Discovery, 2014 (b). Survival curves for 16q loss are shown here adapted with permission from Tirode F. et al., Cancer Discovery, 2014 (c). Survival curves for patients stratified by STAG2 and TP53 status, adapted with permission from Tirode F. et al, Cancer Discovery, 2014 (d).

Fig. 3. Prognostic significance of circulating tumor DNA (ctDNA) in Ewing sarcoma.

Here we show that detectable ctDNA at diagnosis is associated with poor outcomes among patients with localized Ewing sarcoma. Adapted with permission from Shulman DS. et al., BJC, 2018.

Fig. 4. Hypothetical risk-stratified treatment schema.

We provide a hypothetical risk-stratification schema that one could envision as the biomarkers described in this manuscript are validated. This schema incorporates clinical and molecular biomarkers.